The Role of transcription factor Sox2 in the homeostasis of the adult esophagus

描述（由申请人提供）：食管疾病，包括巴雷特食管（BE）、腺癌和鳞癌是工业社会中严重的健康问题。然而，对这些疾病的分子机制知之甚少。我以前使用小鼠模型的研究表明，转录因子Sox 2对食管的正常发育至关重要。在成人食管中，Sox 2在基底祖细胞中以高水平表达，但其在该阶段的功能仍然未知。有趣的是，在人类中，食管中SOX 2蛋白水平的降低与BE的发生有关。我的假设是Sox 2调节成人食管的稳态，并且Sox 2的精确水平是食管上皮正常增殖和分化所必需的。此外，我假设Sox 2调控网络的破坏是多因素疾病（如BE和癌症）进展的主要组成部分。为了验证这一假设，我将首先在小鼠食管的上皮细胞中特异性地删除和过表达Sox 2。然后，我将检查表型变化，并研究导致异常的潜在机制。此外，我以前的工作表明，骨形态发生蛋白（Bmp）信号通路抑制Sox 2在前肠的表达。最近，上调这一信号通路已牵连在BE的发展。因此，我的第二个目的是检验Sox2上游BMP信号传导缺陷导致食管疾病的假设。我将首先研究增加BMP信号对从成年小鼠食管分离的培养基底细胞的影响。然后，我将异位激活BMP信号在小鼠食管的基底细胞在体内，并分析表型的变化，包括对Sox2表达的潜在影响。总之，这些研究将提供关键信息的需求Sox2和BMP信号的稳态成人食管。它们可能对制定食管疾病的治疗策略有意义。 公共卫生相关性：该提案与食管疾病直接相关。Barrett食管、食管腺癌的发病率近二十年来有明显上升。利用小鼠模型系统研究成人食管内环境稳定的分子机制将有助于开发治疗食管疾病的战略疗法。

DESCRIPTION (provided by applicant): Esophageal diseases, including Barrett's esophagus (BE), adenocarcinoma and squamous cancers are serious health problems in industrial societies. However, relatively little is known about the molecular mechanisms underlying these disorders. My previous studies using mouse models demonstrated that the transcription factor, Sox2, is essential for the normal development of the esophagus. In the adult esophagus Sox2 is expressed at high levels in basal progenitor cells, but its function at this stage remains unknown. Interestingly, in humans decreased SOX2 protein levels in the esophagus have been associated with the development of BE. My hypothesis is that Sox2 regulates the homeostasis of the adult esophagus, and that precise levels of Sox2 are required for normal proliferation and differentiation of the esophageal epithelium. Moreover, I hypothesize that disruption of the Sox2 regulatory network is a major component of the progression of multifactorial diseases such as BE and cancer. To test this hypothesis, I will first delete and overexpress Sox2 specifically in the epithelial cells of the mouse esophagus. I will then examine phenotypic changes and study the underlying mechanisms leading to the abnormalities. In addition, my previous work suggested that bone morphogenetic protein (Bmp) signaling pathway suppresses Sox2 expression in foregut. Recently, upregulation of this signaling pathway has been implicated in the development of BE. My second aim therefore is to test the hypothesis that defects in Bmp signaling upstream of Sox2 contribute to esophageal disorders. I will start by examining the effect of increased Bmp signaling on cultured basal cells isolated from the adult mouse esophagus. I will then ectopically activate Bmp signaling in the basal cells of the mouse esophagus in vivo, and analyze the phenotypic changes, including potential effects on Sox2 expression. Taken together these studies will provide critical information on the requirements of Sox2 and Bmp signaling for the homeostasis of the adult esophagus. They may have implications for devising therapeutic strategies for esophageal diseases. PUBLIC HEALTH RELEVANCE: This proposal has direct relevance to esophageal diseases. The incidence of Barrett's esophagus, esophageal adenocarcinoma has increased significantly in recent two decades. Studying the molecular mechanisms underlying the homeostasis of the adult esophagus using mouse model systems will facilitate the development of strategic therapies for treating esophageal disease.